POS0242 RESPONSE TO ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTS REQUIRES A SPECIFIC MACROPHAGE POLARISATION
Authors: B. De Maleprade, B. Gerard, P. Brevet, S. Candon, O. Vittecoq, M. Freret, T. Lequerre
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Abatacept (ABA), a biologic treatment for rheumatoid arthritis (RA), is a recombinant fusion protein composed of the extracellular domain of human CTLA-4 combined with the Fc portion of human IgG1. Lack of response to treatment occurs in 30 % of RA patients, highlighting the need to better understanding its mechanism of action and to identify predictive factors of response. Although ABA is considered to interrupt the costimulatory signal, the importance of this mechanism on the drug effect lacks evidence. Moreover, therapies targeting T cells were disappointing in RA [1]. In contrast, ABA has been shown to induce reverse signaling in antigen-presenting cells, by activating the indolamine 2,3-dioxygenase (IDO) pathway (a strong tolerogenic enzyme) in macrophages and dendritic cells [2]. ABA also acts on nitric oxide (NO) production, a proinflammatory molecule capable of inhibiting IDO action, although conflicting data have been reported. <h3>Objectives</h3> The objective of this study was to evaluate the importance of direct mechanisms on antigen-presenting cells and identify biomarkers of the response to ABA. <h3>Methods</h3> Sera (n = 71) and RNA from whole blood (n = 57) were collected from RA patients before treatment by ABA. Abundance of GM-CSF, gamma interferon (IFNg), IL-10, IDO, iNOS were quantified using ELISA and addressable laser bead assay (ALBIA). RT-qPCR was performed on <i>IDO1</i> transcript. Response to ABA was assessed 6 months after its introduction, using EULAR response criteria. A costimulation <i>in vitro</i> model was developed: monocytes-derived macrophages (using GM-CSF or M-CSF) from healthy donors were polarized 8 days with LP, with or without IFNg. T cells were cocultured with anti-CD3, with or without ABA, anti-CD28 antibodies or IDO inhibitor (1-MTDT). Proliferation was assessed using CFSE. <h3>Results</h3> Before ABA therapy, GM-CSF, IFNg and IL-10 in sera were increased in serum of good responders compared to non-responders. Our costimulation model showed that in macrophages exposed to GM-CSF, IFNg, LPS, ABA inhibited lymphocyte proliferation by 53%. Inhibition by ABA was only 10% when macrophages has not been exposed to IFNg, suggesting a central role of this cytokines. Furthermore, inhibition was only achieved when both GM-CSF + IFNγ were used, highlighting the need for a combination of these two factors. In presence of GM-CSF with IFNg + LPS + ABA, IDO was increased in macrophages. ABA increased iNOS production in macrophages when either IFNg or GM-CSF were not involved in their polarisation, neutralising IDO and leading to T cell proliferation. These results show a balance between iNOS and IDO in macrophages, modulated by IFNγ and GM-CSF. In RA patients, ABA could release the tolerogenic potential of polarized macrophages, decreasing T cell proliferation. Accordingly, iNOS increased in non-responders‘ sera after 6 months of ABA treatment while <i>IDO1</i> expression increased in good responders whole blood RNA. In fact, in ABA responders, IDO increase in macrophages enabling a tolerogenic effect since iNOS is not induced. <h3>Conclusion:</h3> Specific macrophage polarisation with IFNg and GM-CSF, leading to an increase in IDO production without increasing iNOS after treatment, could be the key to achieving a good response to ABA. This finding supports the macrophage-mediated action of ABA and may contribute to the development of a prediction system for abatacept response based on macrophage polarisation. <h3>References</h3> [1]Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 Costimulatory Pathways in Autoimmunity and Transplantation. Annu Rev Immunol 2001;19:225–52. doi:10.1146/annurev.immunol.19.1.225 [2]Bozec A, Luo Y, Engdahl C, et al. Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner. Arthritis Res Ther 2018;20:24. doi:10.1186/s13075-018-1527-x <h3>Acknowledgements</h3> Study conducted with the financial support of the Société Française de Rhumatologie. <h3>Disclosure of Interests</h3> Baptiste de Maleprade: None declared, Baptiste Gerard: None declared, Pauline Brevet: None declared, Sophie Candon: None declared, Olivier VITTECOQ Consultant of: AbbVie, Bristol-Myers Squibb, Gilead, Lilly, Merck, Novartis, Pfizer, Roche- Chugai, Mylan and Sanofi, Grant/research support from: Novartis, Pfizer, Merck and Bristol-Myers Squibb, Manuel Freret: None declared, Thierry Lequerre Speakers bureau: AbbVie, Boehringer Ingelheim, BMS, Fresenius, Galapagos, Lilly, MEDAC, MSD, Nordic Pharma, Novartis, Pfizer, Roche – Chugai, UCB.